AEROSOLS Pharmaceutical aerosols are pressurized dosage forms that

AEROSOLS

• Pharmaceutical aerosols are pressurized dosage forms that upon actuation emit a fine dispersion of liquid and/or solid materials containing one or more active ingredients in a gaseous medium. • They differ from most other dosage forms in their dependence upon the function of the container, its valve assembly, and an added component— the propellant—for the physical delivery of the medication in proper form.

• The term pressurized package is commonly used when referring to the aerosol container or completed product. • Pressure is applied to the aerosol system through the use of one or more liquefied or gaseous propellants. • Upon activation of the valve assembly of the aerosol, the pressure exerted by the propellant forces the contents of the package out through the opening of the valve.

• They are intended for local action in the nasal area, the throat and the lungs as well as for systemic effect when absorbed from the lungs in to the blood stream (inhalation or aerosol therapy).

• Aerosol products may be designed to expel their contents as a fine mist; a coarse, wet, or dry spray; a steady stream; or a stable or a fast-breaking foam. • The physical form selected for a given aerosol is based on intended use. • For instance, an aerosol for inhalation therapy, as in the treatment of asthma or emphysema, must present particles in the form of a fine liquid mist or as finely divided solid particles. Particles less than 6 μm will reach the respiratory bronchioles, and those less than 2 μm will reach the alveolar ducts and alveoli.

Relationship of INTAL (cromolyn sodium, Fisons) particle size to airway penetration.

• By contrast, the particle size for a dermatologic spray intended for deposition on the skin is coarser and generally less critical to therapeutic efficacy of the product. • Some dermatologic aerosols present the medication in the form of a powder, a wet spray, a stream of liquid (usually a local anesthetic), or an ointment-like product. Other pharmaceutical aerosols include vaginal and rectal foams.

• Aerosols used to provide an airborne mist are termed space sprays. Room disinfectants, room deodorizers, and space insecticides characterize this group of aerosols. • The particle size of the released product is generally quite small, usually below 50 μm, and must be carefully controlled so that the dispersed droplets or particles remain airborne for a long time. A 1 -second burst from a typical aerosol space spray will produce 120 million particles, a substantial number of which will remain suspended in the air for an hour.

• The dermatologic aerosols can be placed in this group. Also included are cosmetic and household aerosol products, including personal deodorant sprays, hair lacquers and sprays, perfumes and colognes, shaving lathers, toothpaste, surface pesticide sprays, paint sprays, spray starch, waxes, polishes, cleaners, and lubricants. • A number of veterinary and pet products have been put into aerosol form, as have such food products as dessert toppings and food spreads. Some of these products are sprays; others, foams; and a few, pastes.

ADVANTAGES OF THE AEROSOL DOSAGE FORM • 1. A portion of medication may be easily withdrawn from the package without contamination or exposure to the remaining material. • 2. By virtue of its hermetic character, the aerosol container protects medicinal agents adversely affected by atmospheric oxygen and moisture. Being opaque, the usual aerosol container also protects drugs adversely affected by light. This protection persists during the use and the shelf life of the product. If the product is packaged under aseptic conditions, sterility may also be maintained during the shelf life of the product.

• 3. Topical medication may be applied in a uniform thin layer to the skin without anything else touching the affected area. This method of application may reduce the irritation that sometimes accompanies mechanical (fingertip) application of topical preparations. The rapid volatilization of the propellant also provides a cooling, refreshing effect. • 4. By proper formulation and valve control, the physical form and the particle size of the emitted product may be controlled, which may contribute to the efficacy of a drug, as with the fine controlled mist of an inhalant aerosol. Through the use of metered valves, dosage may be controlled. • 5. Aerosol application is a clean process, requiring little or no washup by the user.

Components of Aerosol Package (1) Propellant. (2) Container. (3) Valve and actuator. (4) Product concentrates.

Propellants • Propellants Is a liquefied gas with a vapor pressure greater than atmospheric pressure at a temperature of 105˚ F (40. 5 ˚C) Physicochemical properties of propellants: • The propellant is one of the most important components of the aerosol package (It is said to be the heart of the aerosol). • It provides the necessary force to expel the contents; it causes the product to be dispensed as foam or a spray, depending on the formulation. • It serves as a solvent for certain active ingredient.

The propellant used for aerosols include: 1) Liquefied gases. A. Fluorinated hydrocarbons (halocarbons) (Chlorofluorocarbons [CFCs]). trichloromonofluoromethane (propellant 11) dichlorodifluoromethane (propellant 12) dichlorotetrafluoroethane (propellant 114) B. Hydrocarbons. (propane, butane, and iso butane) 2) Compressed gases. Ø Nitrogen. Ø Nitrous oxide. Ø Carbon dioxide.

THE AEROSOL PRINCIPLE • An aerosol formulation consists of two component parts: the product concentrate and the propellant. • The product concentrate is the active ingredient of the aerosol combined with the required adjuncts, such as antioxidants, surface active agents, and solvents, to prepare a stable and efficacious product. • When the propellant is a liquefied gas or a mixture of liquefied gases, it frequently serves the dual role of propellant and solvent or vehicle for the product concentrate. • In certain aerosol systems, compressed gases— carbon dioxide, nitrogen, and nitrous oxide—are employed as the propellant.

• For many years, the liquefied gas propellants most used in aerosol products were the chlorofluorocarbons (CFCs). However, these propellants are being phased out and will be prohibited for nonessential use under federal regulations following recognition that they reduce the amount of ozone in the stratosphere, which results in an increase in the amount of ultraviolet radiation reaching the earth, an increase in the incidence of skin cancer, and other adverse environmental effects.

• Under the law, the FDA has the authority to exempt from the prohibition specific products under the agency’s jurisdiction when there is sufficient evidence showing that • (a) there are no technically feasible alternatives to the use of a CFC propellant in the product; • (b) the product provides a substantial health or other public benefit unobtainable without the use of the CFC; • (c) the use does not involve a significant release of CFCs into the atmosphere or, if it does, the release is warranted by the benefit conveyed.

• Among the CFCs used as propellants in pharmaceuticals were dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane. • Fluorinated hydrocarbons are gases at room temperature. They may be liquefied by cooling below their boiling point or by compression at room temperature. • For example, dichlorodifluoromethane (Freon 12) will form a liquid when cooled to − 30°C (− 22°F) or when compressed to 70 psig (pounds per square inch gauge) at 21°C (70°F). Both of these methods for liquefying gases are employed in aerosol packaging.

PHYSICAL PROPERTIES OF SOME FLUORINATED HYDROCARBON PROPELLANTS

Blends of various fluorocarbon propellants are generally used for pharmaceutical aerosols By varying the proportion of each component, any desired vapor pressure can be achieved within the limits of the vapor pressure of the individual propellants.

• Example: • The vapor pressure of pure CFC 11 (molecular weight 137. 4) at 21°C is p 11° = 13. 4 lb/in 2 (psi) and that of CFC 12 (molecular weight 120. 9) is p 12° = 84. 9 psi. • What is the partial pressure of CFCs 11 and 12 in the 50: 50 mixture, and what is the total vapor pressure of this mixture?

• A 50: 50 mixture by gram weight of the two propellants consists of: • 50 g ÷ 137. 4 g/mole = 0. 364 mole of CFC 11 • 50 g ÷ 120. 9 g/mole = 0. 414 mole of CFC 12.

• The total vapor pressure of the mixture is

• When a liquefied gas propellant or propellant mixture is sealed within an aerosol container with the product concentrate, equilibrium is quickly established between the portion of propellant that remains liquefied and that which vaporizes and occupies the upper portion of the aerosol container. • The vapor phase exerts pressure in all directions— against the walls of the container, the valve assembly, and the surface of the liquid phase, which is composed of the liquefied gas and the product concentrate.

• It is this pressure that upon actuation of the aerosol valve forces the liquid phase up the dip tube and out of the orifice of the valve into the atmosphere. • As the propellant meets the air, it expands and evaporates because of the drop in pressure, leaving the product concentrate as airborne liquid droplets or dry particles, depending upon the formulation.

• As the liquid phase is removed from the container, equilibrium between the propellant remaining liquefied and that in the vapor state is reestablished. • Thus, even during expulsion of the product from the aerosol package, the pressure within remains virtually constant, and the product may be continuously released at an even rate and with the same propulsion. • However, when the liquid reservoir is depleted, the pressure may not be maintained, and the gas may be expelled from the container with diminishing pressure until it is exhausted.

Cross-section sketches of contents and operation of a typical two-phase aerosol system

AEROSOL SYSTEMS • The pressure of an aerosol is critical to its performance. It can be controlled by • (a) the type and amount of propellant and • (b) the nature and amount of product concentrate. • Space sprays generally contain a greater proportion of propellant than do aerosols intended for surface coating.

• Space aerosols usually operate at 30 to 40 psig at 21°C and may contain as much as 85% propellant. • Surface aerosols commonly contain 30% to 70% propellant with pressures between 25 and 55 psig at 21°C. • Foam aerosols usually operate between 35 and 55 psig at 21°C and may contain only 6% to 10% propellant.

• Foam aerosols may be considered to be emulsions, because the liquefied propellant is partially emulsified with the product concentrate rather than being dissolved in it. • Because the fluorinated hydrocarbons are nonpolar organic solvents having no affinity for water, the liquefied propellant does not dissolve in the aqueous formulation. • The use of surfactants or emulsifiers in the formulation encourages the mixing of the two components to enhance the emulsion. • Shaking of the package prior to use further mixes the propellant throughout the product concentrate. • When the aerosol valve is activated, the mixture is expelled to the atmosphere, where the propellant globules vaporize rapidly, leaving the active ingredient in the form of a foam.

• Blends of the various liquefied gas propellants are generally used in pharmaceutical aerosols to achieve the desired vapor pressure and to provide the proper solvent features for a given product. • Some propellants are eliminated from use in certain products because of their reactivity with other formulative materials or with the proposed container or valve components. • For instance, trichloromonofluoromethane tends to form free hydrochloric acid when formulated with systems containing water or ethyl alcohol, the latter a commonly used cosolvent in aerosol systems. The free hydrochloric acid not only affects the efficacy of the product but also corrodes some container components.

1. Two Phase Systems • the two-phase aerosol system consists of the liquid phase, containing the liquefied propellant and product concentrate, and the vapor phase.

2. Three Phase Systems • The three-phase system consists of a layer of water-immiscible liquid propellant, a layer of highly aqueous product concentrate, and the vapor phase. • Because the liquefied propellant usually has a greater density than the aqueous layer, it generally resides at the bottom of the container with the aqueous phase floating above it. • To avoid expulsion of the reservoir of liquefied propellant, the dip tube must extend only within the aqueous phase (product concentrate) and not down into the layer of liquefied propellant. The aqueous product is broken up into a spray by the mechanical action of the valve.

• If the container is shaken immediately prior to use, some liquefied propellant may be mixed with the aqueous phase and be expelled through the valve to facilitate the dispersion of the exited product or the production of foam. • The vapor phase within the container is replenished from the liquid propellant phase.

3. Compressed Gas Systems • Compressed rather than liquefied gases may be used to prepare aerosols. • The pressure of the compressed gas in the head space of the aerosol container forces the product concentrate up the dip tube and out of the valve. • The use of gases that are insoluble in the product concentrate, as is nitrogen, will result in emission of a product in essentially the same form as it was placed in the container.

• An advantage of nitrogen as a propellant is its inert behavior toward other formulative components and its protective influence on products subject to oxidation. • Also, nitrogen is an odorless and tasteless gas and thus does not contribute adversely to the smell or taste of a product

• Other gases, such as carbon dioxide and nitrous oxide, which are slightly soluble in the liquid phase of aerosol products, may be employed when their expulsion with the product concentrate is desired to achieve spraying or foaming.

AEROSOL CONTAINER AND VALVE ASSEMBLY • The formulation must not chemically interact with the container or valve components so as to interfere with the stability of the formulation or with the integrity and operation of the container and valve assembly. • The container and valve must be capable of withstanding the pressure required by the product, it must resist corrosion, and the valve must contribute to the form of the product to be emitted.

Containers • Various materials have been used in the manufacture of aerosol containers, including • (a) glass, uncoated or plastic coated; • (b) metal, including tin-plated steel, aluminum, and stainless steel; • (c) plastics. • The selection of the container is based on its adaptability to production methods, compatibility with formulation components, ability to sustain the pressure intended for the product, the interest in design and aesthetic appeal on the part of the manufacturer, and cost.

• Glass presents fewer problems with respect to chemical compatibility with the formula than do metal containers, and it is not subject to corrosion. Glass is also more adaptive to creativity in design. • On the negative side, glass containers must be precisely engineered to provide the maximum in pressure safety and impact resistance.

• Tin-plated steel containers are the most widely used metal containers for aerosols. • When required, special protective coatings are employed within the container to prevent corrosion and interaction between the container and formulation.

• Plastic coatings are commonly applied to the outer surface of glass containers to render them more resistant to accidental breakage, and in the event of breaking, the plastic coating prevents the scattering of glass fragments. • When the total pressure of an aerosol system is below 25 psig and no more than 50% propellant is used, glass containers are considered quite safe. • Plastic containers have met with varying success in the packaging of aerosols because of their inherent problem of being permeated by the vapor within the container. • Also, certain drug– plastic interactions affect the release of drug from the container and reduce the efficacy of the product.

Valve Assembly • The function of the valve assembly is to permit expulsion of the contents of the can in the desired form, at the desired rate, and in the case of metered valves, in the proper amount or dose. • The materials used in the manufacture of valves must be inert to the formulations and must be approved by the FDA. Among the materials used in the manufacture of the various valve parts are plastic, rubber, aluminum, and stainless steel. • The usual aerosol valve assembly is composed of the following parts:

• The usual aerosol valve assembly is composed of the following parts: • • 1. Actuator 2. Stem 3. Gasket 4. Spring 5. Mounting cup 6. Housing 7. Dip tube

holds the valve in place. Supports the actuator prevents leakage of the Formulation Holds the gasket in place and returning the valve to the closed position. brings the formulation from the container to the valve. links the dip tube and the stem and actuator. With the stem, determine the delivery rate

Actuators • To ensure that the aerosol product is delivered in the proper and desired form, a specially designed button or actuator must be fitted to the valve stem. • The actuator allows for easy opening and closing of the valve and is an integral part of almost every aerosol package.

Actuators types: 1. Spray. (Various openings 1 -3) 2. Foam. (Large orifices) 3. Solid stream. (Large opining – as ointment) 4. Special applications. (They are designed to deliver the medication to the appropriate site of action - throat, nose, eye, or vaginal tract).

Various actuators and applicators

Actuator • The Actuator button the user presses to activate the valve assembly for emission of the product. • The design of the inner chamber and size of the emission orifice of the actuator contribute to the physical form (mist, coarse spray, solid stream, or foam) in which the product is discharged. • The type and quantity of propellant used and the actuator design and dimensions control the particle size of the emitted product. • Larger orifices (and less propellant) are used for products to be emitted as foams and solid streams than for those intended to be sprays or mists.

METERED DOSE INHALERS

Metered dose inhalers • Metered-dose inhalers (MDIs) are the most commonly used inhalation drug delivery devices.

• Metering valves are employed when the formulation is a potent medication, as in inhalation therapy. • the amount of material discharged is regulated by an auxiliary valve chamber by virtue of its capacity or dimensions. • A single depression of the actuator causes evacuation of this chamber and delivery of its contents. • The integrity of the chamber is controlled by a dual valve mechanism.

• When the actuator valve is closed, the chamber is sealed from the atmosphere. However, in this position the chamber is permitted to fill with the contents of the container, to which it is open. • Depression of the actuator causes a simultaneous reversal of positions; the chamber becomes open to the atmosphere, releasing its contents, at the same time becoming sealed from the contents of the container. • Upon release of the actuator, the system is restored for the next dose.

• the effectiveness of delivering medication to the lower reaches of the lungs for local or systemic effects depends in part on • the particle size of the inhaled drug. • Breathing patterns • the depth of respiration

• The patient should understand that coordination must be achieved between inhalation (after exhaling as completely as possible) and pressing down the inhaler to release one dose. • The patient should be instructed to hold the breath for several seconds or as long as possible to gain the maximum benefit from the medication, then remove the inhaler from the mouth and exhale slowly through pursed lips.

Method of use therapeutic inhalation aerosols 1. The cap should be removed and inhaler shaken to dispense the drug. 2. The patient should breathe out normally, but not fully. The inhaler mouthpiece is then put in the mouth and the lips closed round it.

3. The patient then breathes in slowly and at the same time activates the aerosol by pressing down on the canister. 4. The breath should be held for 10 seconds or as long as the patient can comfortably manage. 5. The patient then slowly exhales. 6. If another dose has to be taken at least 1 minute should elapse before repeating the exercise.

• If the patient cannot use the inhaler, it is advisable to recommend the use of an extender device with the inhaler. • Extender devices, or spacers, were originally developed for patients who could not learn to coordinate release of the medication with inhalation.

• By placing an extender device between the metereddose inhaler’s mouthpiece and the patient’s mouth, the patient is permitted to separate activation of the aerosol from inhalation by up to 3 to 5 seconds (a valve in the spacer opens when the patient inhales). • Another advantage of the extender is that aerosol velocity is reduced and droplet size is decreased because there is time for evaporation of the fluorohydrocarbon propellant. Thus, extender devices also cause less deposition of medication in the oropharynx.

• A unique translingual aerosol formulation of nitroglycerin (Nitrolingual Spray, Rhône-Poulenc Rorer) permits a patient to spray droplets of nitroglycerin onto or under the tongue for acute relief of an attack or for prophylaxis of angina pectoris. • The product is not to be inhaled. • At the onset of an attack, two metered spray emissions, each containing 0. 4 mg of nitroglycerin, are administered. • The product contains 200 doses of nitroglycerin in a propellant mixture of dichlorodifl uoromethane and dichlorotetrafluoroethane.

Storage of aerosols • Store in cool place. • Protect from heat, sun. • Not freeze. Advice to patient • (Not exceed the recommended dose).